Orexin is a brain neuropeptide produced in lateral hypothalamus. Two types of orexins, orexin A (hereinafter referred to as “OX-A”; 33 amino acid residues) and orexin B (hereinafter referred to as “OX-B”; 28 amino acid residues), are known to be produced by enzymatic cleavage of the common precursor preproorexin. Moreover, two types of G protein-coupled receptors, orexin 1 (hereinafter referred to as “OX1”) receptor and orexin 2 (hereinafter referred to as “OX2”) receptor, are known as receptors for orexin, and OX1 and OX2 receptors are understood to be coupled to Gq and Gq as well as Gi/o, respectively. OX-A activates OX1 and OX2 receptors with similar potencies, while OX-B relatively selectively activates OX2 receptor (Non-Patent Document 1). It is understood that putative physiological effects of orexin are exerted through either one or both of OX1 and OX2 receptors.
Orexin is known to play important roles in regulation of feeding behavior and maintenance of sleep and wakefulness, which are essential for life, and is involved in control of energy metabolism and glucose metabolism. For example, it has been observed that the expression of orexin is increased in mice or rats which are fasted, while intracerebral administration of orexin increases food intake in mice or rats. Moreover, orexin is reportedly a factor which causes changes in level of wakefulness and in emotion, depending on a metabolic state in human, and thus induces feeding, and is understood to be involved in many aspects of pathophysiology, such as obesity, eating disorder, and sleep disorder (Non-Patent Documents 2 and 3). Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, sudden loss of muscle strength in response to strong emotions, hallucinations while falling asleep, and sleep paralysis. It is a disease which also shows attention deficit hyperactivity disorder (ADHD)-like symptoms, and is reported to be caused by insufficiency of the orexin neuronal system (Non-Patent Document 4).
Also, an orexin receptor antagonist is reported to exhibit antidepressant-like effects in mouse models of depression (Non-Patent Document 5). Moreover, a recent study using OX1 receptor knock-out mice and an OX1 receptor antagonist has indicated the potential of a compound that has an inhibitory effect on OX1 receptor as a candidate therapeutic agent for addiction and misuse of drugs, including ethanol, nicotine, cocaine, cannabinoid, and morphine, and for hyperphagia and anxiety disorder (Non-Patent Document 6). Furthermore, the potential of a compound that has an inhibitory effect on OX1 receptor as a candidate therapeutic agent for panic disorder, such as panic attack and the resulting anticipatory anxiety, has also been reported (Non-Patent Document 7).
Furthermore, it is reported that orexin receptors can be involved in various pathologic conditions, such as depression, anxiety disorder, dependence, obsessive-compulsive disorder, emotional neurosis, depressive neurosis, anxiety neurosis, dysthymic disorder, behavioral disorder, mood disorder, sexual dysfunction, mental dysfunction, hypogonadism, schizophrenia, manic depression, delirium, dementia, severe mental retardation and movement disorders (such as, for example, Huntington's disease and Tourette syndrome), feeding disorder (such as, for example, hypophagia, hyperphagia, plague, and obesity), addictive eating behaviors (such as, for example, overeating/vomiting behavior), cardiovascular disease, diabetes mellitus, appetite/taste disorder, emesis, vomiting, nausea, asthma, cancer, Parkinson's disease, Cushing syndrome/disease, basophilic adenoma, prolactinoma, hyperprolactinemia, pituitary gland tumor/adenoma, hypothalamic disease, inflammatory bowel disease, gastric dyskinesia, gastric ulcer, Froehlich's syndrome, adrenohypophysis disease, pituitary disease, adrenohypophysis hypoactivity, adrenohypophysis hyperactivity, hypothalamic hypogonadism, Kallmann syndrome (such as, for example, dysosmia and hyposmia), functional or psychogenic amenorrhea, pituitary hypoactivity, hypothalamic hypothyroidism, hypothalamic adrenal insufficiency, idiopathic hyperprolactinemia, growth hormone insufficiency as a hypothalamic disease, idiopathic developmental retardations, dwarfism, gigantism, acromegaly, biological and circadian rhythm defect, neurological disorder, sleep disorder associated with neuropathic pain and a disease such as restless legs syndrome, cardiopulmonary disease, acute and congestive heart failure, hypotension, hypertension, urinary retention, osteoporosis, angina pectoris, myocardial infarction, ischemic or hemorrhagic stroke, subarachnoid hemorrhage, ulcer, allergies, benign prostatic hypertrophy, chronic renal failure, kidney disease, reduced glucose tolerance, migraine, hyperalgesia, pain, hyperpathia, enhanced or excessive hypersensitivity to pain such as burning pain and allodynia, acute pain, burning pain, atypical facial pain, neuropathic pain, back pain, type I and type II complex regional pain syndrome, arthralgia, pain caused by sport injuries, pain associated with infection (such as, for example, infection of HIV), chemotherapy-induced pain, central post-stroke pain, post-surgery pain, neuralgia, visceral pain in irritable bowel syndrome or the like and the state associated with angina pectoris, bladder incontinence (such as, for example, urgent incontinence), narcotic drug tolerance or withdrawal from narcotic drug addiction, sleep disorder, sleep apnea, narcolepsy, insomnia, parasomnia, jet lag syndrome, neurodegenerative disorders including nosologically classified events (such as, for example, a complex disease consisting of disinhibition, dementia, Parkinson's disease and muscular atrophy, and pallido-ponto-nigral degeneration), epilepsy, seizure disorder, and other diseases related to dysfunction of the orexin system (Patent Document 1).
Thus, there is a great expectation for a compound that exhibits antagonism against orexin receptors to be an agent of preventing or treating sleep disorder, obesity including obesity observed in diabetic patients, eating disorder, anxiety disorder, depression, drug dependence, obsessive-compulsive disorder and attention deficit hyperactivity disorder (ADHD), and other various diseases or symptoms related to orexin receptors.
Various compounds are known to exhibit antagonism against orexin receptors, and, for example, (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-N-methyl-2-phenylacetamide (Almorexant), a derivative of 1,2,3,4-tetrahydroisoquinoline, has been clinically developed as a therapeutic agent for insomnia (Patent Document 2).
Also, [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (Suvorexant, Patent Document 3), a diazepan compound, and (1R,2R)-2-{[2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane carboxamide, a cyclopropane compound, and the like are known to be therapeutic agents for insomnia which exhibit antagonism against orexin receptors (Patent Document 4). Furthermore, various compounds having the antagonistic activity against OX receptors are disclosed in Non-Patent Document 1.
Meanwhile, Non-Patent Document 8 discloses that compounds each having a particular morphinan structure, the compounds exhibiting potent agonism at K-opioid receptor (Patent Document 5), potent antagonism against ORL1 receptor (Patent Document 6) and strong therapeutic effects on drug dependence (Patent Document 7), exhibit a weak antagonistic activity against OX1 receptor.